Quinolones, Folic Acid Antagonists, - PowerPoint Presentation

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Quinolones, Folic

Acid Antagonists,

and Urinary Tract

Antiseptics

I. FLUOROQUINOLONES

Nalidixic

acid is the predecessor to all

fluoroquinolones

, a class of man-

made antibiotics.

Over 10,000

fluoroquinolone

analogs have been synthesized,

Fluoroquinolones

in use today typically offer greater efficacy, a broader spectrum of antimicrobial activity, and a better safety profile than their predecessors.

Unfortunately,

fluoroquinolone

use has been closely tied to Clostridium

difficile

infection and the spread of antimicrobial resistance in many organisms (for example, methicillin resistance in staphylococci).

The unfavorable effects of

fluoroquinolones

on the induction and spread of antimicrobial resistance are sometimes referred to as “collateral damage,” a term which is also associated with third-generation

cephalosporins

(for example,

ceftazidime

).

A. Mechanism of action

Fluoroquinolones

enter bacteria through

porin

channels and exhibit antimicrobial effects on DNA

gyrase

(bacterial topoisomerase II) and

bacterial topoisomerase IV. Inhibition of DNA

gyrase

results in relaxation

of supercoiled DNA, promoting DNA strand breakage.

Inhibitionof

topoisomerase IV impacts chromosomal stabilization during cell

division, thus interfering with the separation of newly replicated DNA.

In gram-negative organisms (for example, Pseudomonas

aeruginosa

), the inhibition of DNA

gyrase

is more significant than that of topoisomerase IV, whereas in gram-positive organisms (for example, Streptococcus

pneumoniae

), the opposite is true.

Agents with higher affinity for topoisomerase IV (for example, ciprofloxacin) should not be used for S.

pneumoniae

infections, while those with more topoisomerase II activity (for example,

moxifloxacin

) should not be used

for P.

aeruginosa

infections.

B. Antimicrobial spectrum

- bactericidal,

-effective against gram-negative organisms (Escherichia coli, P.

aeruginosa

,

Haemophilus

influenzae

),

-atypical organisms (

Legionellaceae

,

Chlamydiaceae

),

-gram-positive organisms (streptococci),

-

some mycobacteria (Mycobacterium tuberculosis).

-

Fluoroquinolones

are typically not used for the treatment of Staphylococcus

aureus

or

enterococcal

infections. They are not effective against syphilis and have limited utility against Neisseria

gonorrhoeae

due to disseminated resistance worldwide.

-

Levofloxacin and

moxifloxacin

are sometimes referred to as “respiratory

fluoroquinolones

,” because they have excellent activity against S.

pneumoniae

, which is a common cause of community-acquired pneumonia (CAP).

-

Moxifloxacin

also has activity against many anaerobes.

-

Fluoroquinolones

are commonly considered alternatives for patients with a documented severe

β-

lactam allergy.

Fluoroquinolones

may be classified into “generations” based on their antimicrobial targets.

-First generation:

nonfluorinated

quinolone

nalidixic

acid is considered to

be,

with a narrow spectrum of susceptible organisms.

-Second generation: Ciprofloxacin

and

norfloxacin

, because

of their activity against aerobic gram-negative and atypical bacteria. In addition, these

fluoroquinolones

exhibit significant intracellular penetration, allowing therapy for infections in which a bacterium spends part or all of its life cycle inside a host cell (for example, chlamydia, mycoplasma, and mycobacteria).

-Third generation: Levofloxacin has increased

activity against gram-positive bacteria.

-Fourth generation: only

moxifloxacin

because of its activity against anaerobic and gram- positive organisms

.

C. Examples of clinically useful

fluoroquinolones

1.

Norfloxacin

:

infrequently prescribed due

to poor oral bioavailability and a short half-life. It is effective

in treating

nonsystemic

infections, such as urinary tract

infections (UTIs

), prostatitis, and infectious diarrhea (unlabeled use

).

2.

Ciprofloxacin

:

effective in the

treatment of many systemic infections caused by

gram-negative bacilli .

-

Of

the

fluoroquinolones

, it has the best

activity against

P.

aeruginosa

and is commonly used in cystic

fibrosis patients

for this indication.

-

With

80% bioavailability, the

intravenous and

oral formulations

are frequently

interchanged.

Although typically dosed twice daily, an extended-release formulation is available for once-daily dosing, which may improve patient adherence to treatment

.

-effective in treatment of

Traveler’s

diarrhea caused

by E. coli as well as typhoid fever caused by

Salmonella

typhi

.

- Second-line

agent in the treatment of

tuberculosis.

3.

Levofloxacin:

the l-isomer of

ofloxacin

and

has largely replaced it clinically.

broad

spectrum of activity,

used for prostatitis

, skin infections,

CAP, and

nosocomial pneumonia. Unlike ciprofloxacin, levofloxacin

has excellent

activity against S.

pneumoniae

respiratory

infections. has

100% bioavailability and is dosed once daily

.

4.

Moxifloxacin

:

has

enhanced activity against gram-positive organisms (for

example, S

.

pneumoniae

) and excellent activity against many anaerobes, although resistance to

Bacteroides

fragilis

has been reported. It has poor activity against P.

aeruginosa

.

Moxifloxacin

does

not concentrate in urine and is not indicated for the treatment of UTIs.

D. Resistance

- chromosomal mutations. Cross-resistance exists among the quinolones. The mechanisms responsible for this resistance:

include the following:

1. Altered target: Chromosomal mutations in bacterial genes (for example,

gyrA

or

parC

) have been associated with a decreased affinity

for

fluoroquinolones

at their site of action. Both topoisomerase IV and DNA

gyrase

may undergo mutations

.

2. Decreased accumulation: Reduced intracellular concentration is linked to:

1)

porin

channels. involves a decreased number of

porin

proteins in the outer membrane of resistant cell.

2) Efflux pumps. it pumps the drug out of the cell

.

E. Pharmacokinetics

1

. Absorption

: Only

35 -

70% of orally administered

norfloxacin

is

absorbed, compared with

80 - 99

% of the other

fluoroquinolones

. Intravenous

and ophthalmic preparations

of ciprofloxacin

, levofloxacin, and

moxifloxacin

are available.

Ingestion of

fluoroquinolones

with

sucralfate

, aluminum- or

magnesium containing

antacids

, or dietary supplements containing

Fe

or

Zn

can

reduce the absorption.

Ca

and other divalent

cations

also interfere

with the absorption of these

agents.

2

.

Distribution:

Binding to plasma proteins ranges from

10 - 40

%.

distribute

well into all tissues and body

fluids, which

is one of their major clinical advantages. Levels are high

in bone

, urine (except

moxifloxacin

), kidney, and prostatic tissue (

but not

prostatic fluid), and concentrations in the lungs exceed those

in serum

. Penetration into cerebrospinal fluid is relatively low

except for

ofloxacin

.

A

lso

accumulate in

macrophages and

polymorphonuclear

leukocytes, thus having activity

against intracellular

organisms

.

3.

Elimination:

Most

fluoroquinolones

are excreted

renally

. Therefore, dosage adjustments are needed in renal dysfunction.

Moxifloxacin

is excreted primarily by the liver, and no dose adjustment is required for renal impairment

.

F. Adverse reactions

-Nausea

, vomiting, and diarrhea.

-

Headache

and dizziness or

lightheadedness may

occur. Thus, patients with central nervous

system (CNS

) disorders, such as epilepsy, should be treated

cautiously with

these drugs. Peripheral

neuropathy.

-Glucose

dysregulation

(hypoglycemia

and

hyperglycemia

) have also been noted.

-

P

hototoxicity

,

use

sunscreen and avoid

excess exposure

to sunlight. If

phototoxicity

occurs, discontinuation

of the

drug is advisable.

-

Articular

cartilage erosion (

arthropathy

), observed

in immature

animals. Therefore

, these agents should be avoided in pregnancy and

lactation and

in children under 18 years of age. [Note: Careful

monitoring is

indicated in children with cystic fibrosis who receive

fluoroquinolones

for

acute pulmonary exacerbations.] An increased risk

of tendinitis

or tendon rupture may also occur with systemic

fluoroquinolone

use

.

-

Moxifloxacin

and other

fluoroquinolones

may

prolong the

QTc

interval and, thus, should not be used in patients

predisposed

to arrhythmias or

taking

other

medications that

cause QT prolongation.

-

Ciprofloxacin

can increase

serum levels

of theophylline by inhibiting its

metabolism, also

raise the serum levels of warfarin,

caffeine, and

cyclosporine

.

II. OVERVIEW OF THE FOLATE ANTAGONISTS

Enzymes requiring

folate

-derived cofactors are essential for the

synthesis of purines and

pyrimidines

(precursors of RNA and DNA) and other compounds necessary

for cellular growth and replication. Therefore, in

the absence

of

folate

, cells cannot grow or divide. To synthesize the

critical

folate

derivative,

tetrahydrofolic

acid, humans must first obtain

preformed

folate

in the form of folic acid from the diet. In contrast, many bacteria are

impermeable to folic acid and other

folates

and, therefore, must rely

on their

ability to synthesize

folate

de novo.

The

sulfonamides (sulfa

drugs) are

a family of antibiotics that inhibit de novo synthesis of

folate

.

A second type

of

folate

antagonist—trimethoprim—prevents

microorganisms from

converting

dihydrofolic

acid to

tetrahydrofolic

acid, with

minimal effect

on the ability of human cells to make this conversion

.

Thus

,

both sulfonamides

and trimethoprim interfere with the ability of an infecting

bacterium to perform DNA synthesis. Combining the sulfonamide

sulfamethoxazole

with trimethoprim (the generic name for the combination

is

cotrimoxazole

) provides a synergistic combination.

III. SULFONAMIDES

The sulfa drugs are seldom prescribed alone except in developing

countries, where

they are still employed because of their low cost and efficacy.

A. Mechanism of action

In many microorganisms,

dihydrofolic

acid is synthesized

from p-

aminobenzoic

acid (PABA),

pteridine

, and

glutamate.

All the sulfonamides currently in clinical use are synthetic analogs

of PABA

. Because of their structural similarity to PABA, the

sulfonamides compete

with this substrate for the bacterial enzyme,

dihydropteroate

synthetase

. They thus inhibit the synthesis of bacterial

dihydrofolic

acid

and, thereby, the formation of its essential cofactor forms.

The sulfa

drugs, including

cotrimoxazole

, are bacteriostatic.

B. Antibacterial spectrum

Sulfa drugs are active against select

Enterobacteriaceae

in the

urinary tract

and

Nocardia

infections. In addition, sulfadiazine

in

combination with the

dihydrofolate

reductase

inhibitor

pyrimethamine

is

the preferred treatment

for toxoplasmosis

.

Sulfadoxine

in combination with

pyrimethamine

is used

as an antimalarial

drug.

C

. Resistance

-Bacteria

that can obtain

folate

from their environment are

naturally resistant

to these drugs.

-

Acquired

bacterial resistance to the

sulfa drugs

can arise from plasmid transfers or random mutations. [

Note: Organisms

resistant to one member of this drug family are

resistant to

all.] Resistance is generally irreversible and may be due

to:

1)an

altered

dihydropteroate

synthetase

.

2) decreased cellular

permeability to

sulfa drugs,

or

3) enhanced production of the

natural substrate

, PABA.

D. Pharmacokinetics

1. Absorption:

After oral administration, most sulfa drugs are well

absorbed.

An exception is

sulfasalazine It

is not absorbed when administered orally or

as a

suppository

and, therefore

, is reserved for treatment of

chronic inflammatory

bowel disease (for example, ulcerative colitis). [

Note: Local

intestinal flora split sulfasalazine into

sulfapyridine

+

5-aminosalicylate

, with the latter exerting the

anti-inflammatory effect

. Absorption of

sulfapyridine

can lead to toxicity in

patients who

are slow

acetylators

.] Intravenous sulfonamides are

generally reserved

for patients who are unable to take oral preparations.

Because of the risk of sensitization, sulfa drugs are not

usually applied

topically. However, in burn units, creams of silver

sulfadiazine or

mafenide

acetate (

α-amino-p-toluene sulfonamide

) have been effective in

reducing burn-associated

sepsis because they prevent colonization

of bacteria

. [Note: Silver sulfadiazine is preferred because

mafenide

produces

pain on application and its absorption may contribute

to acid–base

disturbances.]

2. Distribution:

Sulfa drugs are bound to serum albumin in the

circulation, where

the extent of binding depends on the

ionization constant

(

pKa

) of the drug. In general, the smaller the

pKa

value, the

greater the binding. Sulfa drugs distribute throughout the

bodily fluids

and penetrate well into cerebrospinal fluid—even in

the absence

of inflammation. They can also pass the placental

barrier and

enter fetal tissues.

3. Metabolism:

The sulfa drugs are acetylated and conjugated

primarily in

the liver. The acetylated product is devoid of

antimicrobial activity

but retains the toxic potential to precipitate at neutral

or acidic

pH.

This causes

crystalluria

“

stone formation

” and

, therefore, potential damage to the kidney.

4. Excretion:

Sulfa drugs are eliminated by glomerular

filtration and

secretion and require dose adjustments for renal

dysfunction. Sulfonamides

may be eliminated in breast milk.

E. Adverse effects

1.

Crystalluria

: Nephrotoxicity may develop as a result of

crystalluria

. Adequate

hydration and

alkalinization

of

urine can

prevent the problem by reducing the concentration of drug

and promoting

its ionization.

2. Hypersensitivity: Hypersensitivity reactions, such as rashes,

angioedema or

Stevens-Johnson syndrome, may occur. When

patients report

previous sulfa allergies, it is paramount to acquire a

description of

the reaction to direct appropriate therapy.

3. Hematopoietic disturbances: Hemolytic anemia is

encountered in

patients with glucose-6-phosphate dehydrogenase (G6PD)

deficiency.

Granulocytopenia

and thrombocytopenia can also

occur. Fatal

reactions have been reported from associated

agranulocytosis

, aplastic

anemia, and other blood

dyscrasias

.

4. Kernicterus: This disorder may occur in newborns, because

sulfa drugs

displace bilirubin from binding sites on serum albumin.

The bilirubin

is then free to pass into the CNS, because the

blood–brain barrier

is not fully developed.

5. Drug potentiation: Transient potentiation of the

anticoagulant effect

of warfarin results from the displacement from

binding sites

on serum albumin. Serum methotrexate levels may also

rise through

its displacement.

6. Contraindications: Due to the danger of kernicterus, sulfa

drugs should

be avoided in newborns and infants less than 2 months

of age

, as well as in pregnant women at term. Sulfonamides should

not be given to patients receiving

methenamine

, since they

can crystallize

in the presence of formaldehyde produced by this

agent.

IV. TRIMETHOPRIM

Apotent

inhibitor of bacterial

dihydrofolate

reductase

, exhibits an antibacterial spectrum similar to that

of the

sulfonamides. Trimethoprim is most often compounded with

sulfamethoxazole

, producing

the combination

called

cotrimoxazole

.

A. Mechanism of action

The active form of

folate

is the

tetrahydro

derivative that is

formed through

reduction of

dihydrofolic

acid by

dihydrofolate

reductase

.

This enzymatic

reaction

is

inhibited by trimethoprim,

leading to

a decreased availability of the

tetrahydrofolate

cofactors

required for

purine, pyrimidine, and amino acid synthesis. The bacterial

reductase

has

a much stronger affinity for trimethoprim than does the

mammalian enzyme

, which accounts for the selective toxicity of the drug.

B. Antibacterial spectrum

The antibacterial spectrum of trimethoprim is similar to that of

sulfamethoxazole

. However

, trimethoprim is

20 - 50-fold

more

potent than

the sulfonamides. Trimethoprim may be used alone in the

treatment of

UTIs and in the treatment of bacterial prostatitis (

although

fluoroquinolones

are preferred).

C. Resistance

-Resistance

in gram-negative bacteria is due to the presence of

an altered

dihydrofolate

reductase

that has a lower affinity for trimethoprim.

-Efflux

pumps and decreased permeability to the drug

.

D. Pharmacokinetics

Trimethoprim is rapidly absorbed following oral administration.

Because the

drug is a weak base, higher concentrations of trimethoprim

are achieved

in the relatively acidic prostatic and vaginal fluids.

The drug

is widely distributed into body tissues and fluids, including

penetration into

the cerebrospinal fluid.

Trimethoprim undergoes some O-

demethylation

, but

60 - 80

% is

renally

excreted unchanged

.

E. Adverse effects

Trimethoprim can produce the effects of folic acid deficiency. These effects include

megaloblastic

anemia, leukopenia, and

granulocytopenia

, especially in pregnant patients and those having very poor diets. These blood disorders may be reversed by the simultaneous administration of

folinic

acid, which does not enter bacteria

.

V. COTRIMOXAZOLE

The combination of

trimethoprim +

sulfamethoxazole

, called

cotrimoxazole

, shows

greater antimicrobial activity than

equivalent quantities

of either drug used

alone. The

combination

was selected because of the synergistic activity and the similarity in

the half-lives

of the two drugs.

A. Mechanism of action

The synergistic antimicrobial activity of

cotrimoxazole

results from

its inhibition

of two sequential steps in the synthesis of

tetrahydrofolic

acid

.

Sulfamethoxazole

inhibits the incorporation of PABA into

dihydrofolic

acid

precursors, and trimethoprim prevents reduction of

dihydrofolate

to

tetrahydrofolate

.

B. Antibacterial spectrum

Cotrimoxazole

has a broader spectrum of antibacterial action

than the

sulfa drugs

alone. It

is effective in treating UTIs

and respiratory

tract infections, as well as Pneumocystis

jirovecii

pneumonia (PCP

), toxoplasmosis, and ampicillin- or

chloramphenicol-resistant salmonella

infections. It has activity against MRSA and can be

particularly useful

for community-acquired skin and soft tissue

infections caused

by this organism. It is the drug of choice for infections caused

by susceptible

Nocardia

species and

Stenotrophomonas

maltophilia

.

C. Resistance

Resistance to the trimethoprim–

sulfamethoxazole

combination is

less frequently

encountered than resistance to either of the drugs

alone, because

it requires that the bacterium have simultaneous

resistance to

both drugs. Significant resistance has been documented in a

number of

clinically relevant organisms, including E. coli and MRSA.

D. Pharmacokinetics

Cotrimoxazole

is generally administered

orally. Intravenous administration

may be utilized

in patients

with severe

pneumonia caused

by PCP. Both agents distribute throughout the body.

Trimethoprim concentrates in the relatively acidic milieu of

prostatic fluids

, and this accounts for the use of

trimethoprim–

sulfamethoxazole

in

the treatment of prostatitis.

Cotrimoxazole

readily crosses the

blood–brain

barrier. Both parent drugs and their metabolites are excreted

in the

urine

.

E. Adverse effects

Skin reactions especially in the elderly, nausea

and

vomiting,

g

lossitis

and

stomatitis, hyperkalemia especially

with higher

doses,

m

egaloblastic

anemia, leukopenia, and thrombocytopenia may

be fatal

. The hematologic effects may be reversed by

the concurrent

administration of

folinic

acid, which protects the

patient and

does not enter the microorganism. Hemolytic anemia may

occur in

patients with G6PD deficiency due to the

sulfamethoxazole

component.

Immunocompromised

patients with PCP frequently

show drug-induced

fever, rashes, diarrhea, and/or pancytopenia.

Prolonged

prothrombin

times (increased INR) in patients receiving both

sulfamethoxazole

and warfarin (monitoring). The plasma

half-life of phenytoin may be increased due to inhibition of

its metabolism

. Methotrexate levels may rise due to displacement

from albumin-binding

sites by

sulfamethoxazole

.

VI. URINARY TRACT ANTISEPTICS/ANTIMICROBIALS

UTIs are prevalent in women of child-bearing age and in the

elderly population

. E. coli is the most common pathogen, causing about 80%

of uncomplicated

upper and lower UTIs. Staphylococcus

saprophyticus

is the

second most common bacterial pathogen causing UTIs. In

addition to

cotrimoxazole

and the quinolones previously mentioned, UTIs may

be treated

with any one of a group of agents called urinary tract antiseptics, including

methenamine

,

nitrofurantoin

, and the quinolone

nalidixic

acid.

These

drugs do not achieve

antibacterial levels

in the circulation, but because they

are concentrated

in

the urine

, microorganisms at that site can be effectively eradicated.

A.

Methenamine

Mechanism

of

action:

decomposes at

an acidic pH of 5.5 or less in the urine, thus

producing formaldehyde

, which acts locally and is toxic to most

bacteria. Bacteria

do not develop resistance to

formaldehyde, which

is an advantage of this drug. [Note:

Methenamine

is frequently

formulated with a weak acid (for example,

mandelic

acid or

hippuric

acid) to keep the urine acidic. The urinary pH should

be maintained

below 6. Antacids, such as sodium bicarbonate,

should be

avoided.]

2. Antibacterial spectrum:

is

primarily used for

chronic suppressive

therapy to reduce the frequency of UTIs. Routine use

in patients with chronic urinary catheterization to reduce

catheter associated

bacteriuria

or catheter-associated

UTI is not

generally recommended

.

should

not be used to treat

upper UTIs

(for example, pyelonephritis). Urea-splitting bacteria that

alkalinize the

urine, such as Proteus species, are usually resistant to

the action

of

methenamine

.

3. Pharmacokinetics:

is

administered orally. In

addition to

formaldehyde, ammonium ions are produced in the bladder.

Because the liver rapidly metabolizes ammonia to form

urea,

methenamine

is contraindicated in patients with hepatic

insufficiency, as

ammonia can accumulate.

Distributed throughout

the body fluids, but no decomposition of the

drug occurs

at pH 7.4. Thus, systemic toxicity does not occur, and

the drug

is eliminated in the urine.

4. Adverse effects:

Gastrointestinal distress

,

at

higher doses, albuminuria,

hematuria,

Methenamine

mandelate

is

contraindicated in

patients with renal insufficiency, because

mandelic

acid

may precipitate

. [Note: Sulfonamides, such as

cotrimoxazole

, react

with formaldehyde

and must not be used concomitantly with

methenamine

. The

combination increases the risk of

crystalluria

and

mutual antagonism.]

B.

Nitrofurantoin

S

ensitive

bacteria

reduce the

drug to a highly active intermediate that inhibits various enzymes

and damages bacterial DNA. It is useful against E. coli, but

other common

urinary tract gram-negative bacteria may be resistant.

Grampositive

cocci

(for example, S.

saprophyticus

) are typically susceptible.

Hemolytic anemia may occur with

nitrofurantoin

use in

patients with

G6PD deficiency. Other adverse effects include

gastrointestinal disturbances

, acute pneumonitis, and neurologic problems.

Interstitial pulmonary

fibrosis has occurred in patients who take

nitrofurantoin

chronically

. The drug should not be used in patients with

significant renal

impairment or women who are 38 weeks or more pregnant.